title: False-positive results obtained from the branch-site test of positive selection.
abstract: Natural selection operating at the amino acid sequence level can be detected by comparing the rates of synonymous (r(S)) and nonsynonymous (r(N)) nucleotide substitutions, where r(N)/r(S) (omega) > 1 and omega < 1 suggest positive and negative selection, respectively. The branch-site test has been developed for detecting positive selection operating at a group of amino acid sites for a pre-specified (foreground) branch of a phylogenetic tree by taking into account the heterogeneity of omega among sites and branches. Here the performance of the branch-site test was examined by computer simulation, with special reference to the false-positive rate when the divergence of the sequences analyzed was small. The false-positive rate was found to inflate when the assumptions made on the omega values for the foreground and other (background) branches in the branch-site test were violated. In addition, under a similar condition, false-positive results were often obtained even when Bonferroni correction was conducted and the false-discovery rate was controlled in a large-scale analysis. False-positive results were also obtained even when the number of nonsynonymous substitutions for the foreground branch was smaller than the minimum value required for detecting positive selection. The existence of a codon site with a possibility of occurrence of multiple nonsynonymous substitutions for the foreground branch often caused the branch-site test to falsely identify positive selection. In the re-analysis of orthologous trios of protein-coding genes from humans, chimpanzees, and macaques, most of the genes previously identified to be positively selected for the human or chimpanzee branch by the branch-site test contained such a codon site, suggesting a possibility that a significant fraction of these genes are false-positives.
authors.affiliation: Institute of Molecular Evolutionary Genetics and Department of Biology, The Pennsylvania State University, PA, USA. yossuzuk@lab.nig.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D003062:Codon / Q000235:genetics; D003198:Computer Simulation; D019020:Directed Molecular Evolution / Q000379:methods*; D005189:False Positive Reactions; D006801:Humans; D008251:Macaca / Q000235:genetics; D002679:Pan troglodytes / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D003062:Codon